This invention relates to the modification of long-term potentiation (LTP), learning; memory and/or anxiety states. More particularly, it relates to methods of prophylactically or therapeutically treating LTP, learning, memory and/or anxiety disorders in a patient and to medicaments for use in such methods.
Long-term potentiation (LTP) is a long-sting increase in synaptic efficacy which is induced typically by high-frequency stimulation of afferent fibers (Bliss and Loma 1973). LTP, together with its converse, long-term depression (LTD), is considered an attractive candidate memory storage mechanism.
Consistent with this is an observed association between a severe impairment of LTP and impaired learning and retention of spatial task induced by a selective knockout of functional NMDA receptors in area CA1 of the hippocampus, McHugh et al (1996); Tsien et al (1996).
Impairment of LTP (and of learning/memory) is implicated in, or is the consequence of, a range of disorders. These include, for example, Alzheimer""s Disease and Attention Deficiency Disorder (ADD).
It is an object of this invention to provide a new approach to the modification of the LTP, learning, memory and/or anxiety state in an individual, or at least to provide the public with a useful choice.
The Dtk receptor tyrosine kinase is a member of the Axl subfamily of receptor tyrosine kinases (RTKs) (Crosier, K. E. (1997)). The Axl subfamily currently comprises three members, Ax, Dtk and Mer. These kinases show distinct but overlapping patterns of expression in the adult mouse. with expression to varying extents in neural, reproductive, vascular and haematopoietic tissues (Faust, M. (1992); Neubauer, A. (1994), Crosier, K. E. (1994); Lai et al (1994); Crosier, P. S. (1996); Jia et al (1994); Graham et al (1994); Graham. D. K. (1995)). Dtk is primarily expressed in the adult brain and gonads, with brain expression most prominent in neurons of the cerebellum, neocortex, olfactory bulbs and the CA1 region of the hippocampus (Lai et al (1994); Schulz et al (1995)).
The applicants have now determined that Dtk has a role in hippocampal-dependent learning and memory, primarily through a signalling contribution to LTP induction and maintenance. It is this determination, together with the implications it holds for manipulating LTP and/or learning and memory, which forms the basis of this invention.
The present invention has a number of aspects.
In a first aspect, the invention provides a method of modifying the LTP, learning, memory and/or anxiety state of an individual which comprises the step of manipulating the activity of Dtk receptor tyrosine kinase in the brain of said individual.
In a further aspect, the invention provides a method of prophylactically or therapeutically treating LTP, learning, memory and/or anxiety disorders in a patient which comprises the step of increasing the activity of Dtk receptor tyrosine kinase in the brain of said patient.
In a specific embodiment, said prophylactic or therapeutic result is from maintaining a Dtk receptor tyrosine kinase initiated neuronal anti-apoptotic signal in the brain of said patient.
Preferably, the activity of Dtk receptor tyrosine kinase is increased through administering an effective amount of a stimulatory ligand. As used herein, xe2x80x9cstimulatory ligandxe2x80x9d means a ligand which is capable of both binding to and activating Dtk receptor tyrosine kinase signalling pathway.
In a preferred embodiment, the activity of Dtk receptor tyrosine kinase is increased through administration of the ligand Gas6 or an analog thereof.
In still a further aspect, the invention provides a method of inducing LTP, learning, memory and/or anxiety deficit(s) in an individual which comprises the step of decreasing the activity of Dtk receptor tyrosine kinase in the brain of said individual.
Conveniently, this is achieved by administering to said individual an effective amount of an inhibitory ligand. By xe2x80x9cinhibitory ligandxe2x80x9d it is meant any ligand which is capable of binding to the extracellular binding domain of Dtk receptor tyrosine kinase but which is incapable of activating the signalling pathway.
A decrease in the activity of Dtk receptor tyrosine kinase can also be effected through administration of the extracellular binding domain of Dtk receptor tyrosine kinase in a soluble form.
In yet a further aspect, the invention provides the use of a ligand to Dtk receptor tyrosine kinase in the preparation of a medicament for modifying the LTP, learning, memory and/or anxiety state of an individual.
Preferably, the medicament prepared effects modification of the LTP, learning, memory and/or anxiety state of an individual through manipulating the activity of Dtk receptor tyrosine kinase in the brain of said individual.
In yet a further aspect, the invention provides the use of a stimulatory ligand for Dtk receptor tyrosine kinase in the preparation of a medicament for prophylaxis or therapy of LTP, learning, memory and/or anxiety disorder(s).
In still a further aspect, the invention provides the use of a stimulatory ligand for Dtk receptor tyrosine kinase in the preparation of a medicament for inducing a neuronal anti-apoptotic signal within the brain of individual.
In yet a further aspect, the invention provides the use of the ligand Gas6 or an analog thereof in the preparation of a medicament for prophylaxis or therapy of LTP, learning, memory and/or anxiety disorder(s).
In still a further aspect, the invention provides a medicament for use in modifying the LTP, learning, memory and/or anxiety state of an individual which includes a ligand to Dtk receptor tyrosine kinase as defined above.
In still a further aspect, the invention provides a method of identifying a ligand which is capable of modifying the LTP, learning, memory and/or anxiety state of an individual which comprises the step of testing a candidate ligand for its ability to bind and activate the signalling pathway of Dtk receptor tyrosine kinase.
In yet a further aspect, the invention provides a non-human vertebrate animal, which animal normally expresses Dtk receptor tyrosine kinase in the forebrain, which has been modified genetically so that the expression of Dtk receptor tyrosine kinase is at least reduced in the forebrain.
Most preferably, the animal has been modified such that the expression of Dtk receptor tyrosine kinase is eliminated in the forebrain of the animal.
Most preferably, the animal is a mouse.
In still a further aspect, the invention provides a method of identifying a compound which is capable of enhancing LTP, learning and/or memory capability which comprises administering candidate compounds separately to a non-human animal as defined above which has a predetermined baseline LTP/learning/memory deficit and identifying those compounds which enhance LTP, learning and/or memory relative to that baseline.
In yet a further aspect, the invention provides a method of identifying a compound which is capable of reducing or ameliorating an anxiety state which comprises administering candidate compounds separately to a non-human animal as defined above which has a predetermined anxiety quotient and identifying those compounds which reduce anxiety relative to said quotient.